Hypertension affects nearly 50 million Americans; it is a major risk factor for heart disease, stroke and renal failure. Its etiology is mostly unknown, although sodium (Na) retention is a factor underlying much of the susceptibility. In the present application, we seek to identify new mechanisms for hypertension using a strategy where we identify the Na transporters in kidney that account for why blacks retain more Na than whites. Three sites along the nephron will be studied based on compelling evidence that they are linked to the increased Na-retention in blacks: In Specific Aim 1, the Na-K-2CI cotransporter in thick ascending limb; in Specific Aim 2, the thiazide-sensitive Na-Cl cotransporter in distal convoluted tubule; and in Specific Aim 3, the epithelial Na channel in cortical collecting duct. Using genetic markers for these transporters and their regulators, we will test the hypothesis that an increase in the transporter function at any of the sites contributes to the greater retention of Na in blacks. The study cohort consists of blacks and whites, some of whom have been followed with measurements of blood pressure (BP) and body size (every 6-12 months) for as long as 15 years, providing us with important phenotypes of BP regulation. Subjects are young (mean age 20) and, with few exceptions, normotensive (many of them presumably pre-hypertensive). They are without age-related and hypertension-related confounding influences, and free of effects of antihypertensive drugs. We thus explore phenotype with early penetrance, those that may be less evident in older subjects with hypertension. A new interventional study conducted in the General Clinical Research Center - the Saline/Diuretic protocol - allows for the generation of phenotypes (renin and aldosterone levels and BP) in response to major shifts in Na balance. In a subset of subjects in Specific Aim 2., we also assess sensitivity of the BP to a small dose of thiazide diuretic to test the hypothesis that blacks have a more active thiazide-sensitive Na-Cl cotransporter than whites. Using single nucleotide polymorphisms in genes of Na-reabsorptive systems, we examine for linkage disequilibrium with the phenotypes. Additional family members will be recruited (parents and siblings) to extend association studies to the transmission disequilibrium test and to allow for the generation of haplotypes. In summary, by exploring candidate sites for increased Na retention in blacks in comparison to whites, we seek to identify new mechanisms for common forms of hypertension.